Four bipyridine-type ligands variably derivatized with two bioactive groups (taken from ethacrynic acid, flurbiprofen, biotin, and benzylpenicillin) were prepared via sequential esterification steps from commercial 2,2′-bipyridine-4,4′-dicarboxylic acid and subsequently coordinated to ruthenium(II) p-cymene and iridium(III) pentamethylcyclopentadienyl scaffolds. The resulting complexes were isolated as nitrate salts in high yields and fully characterized by analytical and spectroscopic methods. NMR and MS studies in aqueous solution and in cell culture medium highlighted a substantial stability of ligand coordination and a slow release of the bioactive fragments in the latter case. The complexes were assessed for their antiproliferative activity on four cancer cell lines, showing cytotoxicity to the low micromolar level (equipotent with cisplatin). Additional biological experiments revealed a multimodal mechanism of action of the investigated compounds, involving DNA metalation and enzyme inhibition. Synergic effects provided by specific combinations of metal and bioactive fragments were identified, pointing toward an optimal ethacrynic acid/flurbiprofen combination for both Ru(II) and Ir(III) complexes.

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A series of bioactive molecules were synthesized from the condensation of aspirin or chlorambucil with terminal alkynes bearing alcohol or amine substituents. Insertion of the resulting alkynes into the iron–carbyne bond of readily accessible diiron bis(cyclopentadienyl) μ-aminocarbyne complexes, [ 1a , b ]CF 3 SO 3 , afforded novel diiron complexes with a bridging vinyliminium ligand, [ 2 – 10 ]CF 3 SO 3 , functionalized with a bioactive moiety. All compounds were characterized by elemental analysis and IR and multinuclear NMR spectroscopy and in three cases by single-crystal X-ray diffraction. Moreover, the D 2 O solubility, stability in D 2 O and cell culture media, and octanol–water partition coefficients of diiron complexes were determined spectroscopically. The cytotoxicity of the complexes was assessed in the tumorigenic A2780 and A2780cisR and the nontumorigenic HEK 293T cell lines. Some complexes exhibit high potency and the ability to overcome resistance in A2780cisR cells (aspirin complexes) or high selectivity relative to HEK 293T cells (chlorambucil complexes). Further studies indicate that the complexes significantly trigger intracellular ROS production, irrespective of the nature of the bioactive fragment. DNA alkylation and protein binding studies were also undertaken.

Ruthenium(II) complexes with a three-legged piano-stool structure based on an arene ring, an N-heterocyclic carbene (NHC)-carbene ligand with a peracetylated glucose moiety and two chlorides or one bidentate ligand, were prepared and characterized by spectroscopy and crystallography. In one case, the sugar substituent is replaced by an ethyl. The chirality of the sugar results in the formation of two diastereomers that interconvert through rotations around the Ccarbene–Ru and Carene–Ru bonds. In water, the complexes undergo a series of equilibrium hydrolysis steps involving the Ru–Cl bonds. The Ru–arene bond and the sugar acetyls are also partially hydrolyzed, and the selectivity of the process is governed by the nature of the arene and the pH of the solution. The reactivity of the compounds was studied against model nucleophiles and biological macromolecules. In the former case, mass experiments demonstrated a variety of binding modes with a trend reflecting the stability in aqueous environment. In the latter case, protein crystallography was used to characterize the preferential binding sites of one of the complexes. The X-ray structure of the adduct formed upon reaction of one representative complex with hen egg white lysozyme contains a Ru center, which retains the carbene ligand, close to the side chain of Asp119. In the adduct with bovine pancreatic ribonuclease, there are two protein molecules in the asymmetric unit. In one molecule, two Ru centers are located close to the side chains of His105 and of His119, which is the protein active site. In the second molecule, only one Ru center was found in the proximity of the side chain of His105. The Ru complexes also interact with calf-thymus DNA, although without displacing the intercalating probe EB. Finally, the complexes are essentially inactive against the human ovarian carcinoma A2780 cells, the cisplatin-resistant A2780cis cells, and the human embryonic kidney HEK293T cells.

We have recently reported a series of half-sandwich ruthenium(II) complexes with curcuminoid ligands showing excellent cytotoxic activities (particularly ionic derivatives containing PTA (PTA = 1,3,5-triaza-7-phosphaadamantane). In the present study, new...